Abstract / Summary
Abstract Triple-negative breast cancer (TNBC) remains the most difficult breast cancer subtype to treat, being highly invasive and prone to metastasis and recurrence. Conventional chemotherapy is limited by acquired resistance, so new strategies are needed. Based on the concept of synergistic combination therapy, we paired the epigenetic regulator histone deacetylase 6 (HDAC6), which controls the acetylation of multiple proteins, with the transcription factor hypoxia-inducible factor-1α (HIF-1α), which controls the expression of multiple genes. A series of dual-target derivatives was designed and synthesized, and the lead compound 12e was evaluated against panobinostat and sorafenib. 12e exerted multiple anti-breast cancer effects: it was antiproliferative, antimetastatic and antiangiogenic, and it reversed tumour immunosuppression and immune escape. Its antiproliferative effect was comparable to that of panobinostat, its suppression of lung metastasis was comparable to that of sorafenib, and its antiangiogenic effect exceeded that of sorafenib. Mechanistically, dual inhibition of HDAC6 and HIF-1α produced a novel anti-breast cancer mechanism in which multiple signalling pathways and the downstream functional proteins of both targets were synergistically reinforced. The design goal of a multifunctional dual-target antitumour agent was achieved: HDAC6/HIF-1α is a viable target combination for drug discovery, and 12e is a candidate drug for TNBC.